1. Field of the Invention
The present invention relates to a biodegradable polyphosphazene polymer showing a sol-gel behavior by a temperature change in aqueous solution, a preparation method thereof, and injectable thermosensitive polyphosphazene hydrogels using the same.
2. Description of the Related Art
Generally, a hydrogel refers to a three-dimensional network structure formed from a polymer existing in aqueous solution. The hydrogel is formed by a chemical crosslink by a covalent bond or by a physical crosslink through a physical crosslink between molecules.
A network structure formed by the physical crosslink is different from that formed by the chemical crosslink in that the structure is formed not by a crosslinking points like in the covalent bond but by a physical junction zone. A polymer shows a sensitivity against an external stimulus such as temperature, pH, electricity, and etc., and a polymer showing a drastic phase transition by a temperature change is called as a thermosensitive polymer. The thermosensitive polymer shows a phase transition behavior according to a temperature change in aqueous solution, and the phase transition is reversibly performed from sol to gel and from gel to sol according to a temperature change. Especially, in case of a neutral polymer, it is regarded that a physical network structure is formed by a hydrophobic interaction, and the hydrophobic interaction is observed in aqueous solution of a polymer having a side chain such as an aliphatic chain, a fluorine chain, an aromatic chain, etc.
A hydrogel formed by the physical crosslink does not use a chemical crosslinking agent harmful to a body, thereby being spotlighted as a drug delivering material. A polymer showing a sol-gel characteristic by a temperature change includes a poly (N-isopropyl acrylamide), polyethyleneoxide-polypropyleneoxide-polyethyleneoxide (PEO-PPO-PEO) and polyethyleneoxide-polylactic, glycolic acid-polyethyleneoxide (PEO-PLGA-PEO), and etc., and researches for using them as injectable drug delivering material are actively being underway (Advanced Drug Delivery Reviews, 54, 37 (2002), Journal of Controlled Release, 80, 9 (2002)).
However, poly (N-isopropyl acrylamide) is disadvantageous in that it is cytotoxic and not dissolvable in vivo. Also, F127 of the PEO-PPO-PEO (Poloxamer® or Fluronic®) shows a sol-gel behavior by a temperature change in a concentration of not less than about 20% of weight, but when used for a long period, F127 not only increases the concentration of cholesterol in plasma and triglycerides but also is not dissolved in vivo.
PEO-PLGA-PEO(Regel®) is dissolved in a physiological condition and becomes a gel state at a temperature near a body temperature, thereby being researched as an agent for locally delivering an anti-cancer drug. However, that polymer was reported to show a sol-gel characteristic only in a high concentration of more than about 16 weight % (Journal of Controlled Release, 62, 109 (1999)).
The present inventors have reported that polyphosphazene polymers obtained by substituting polydichlorophosphazene with methoxypolyethyleneglycol and amino acid ester are dissolved in water under a predetermined temperature, but have a phase transition behavior in a temperature more than the certain temperature when a temperature is gradually increased and are gradually hydrolyzed in aqueous solution (Macromolecules 32, 2188 (1999), Macromolecules 32, 7820 (1999), Macromolecules 35, 3876 (2002), Korean patent No. 259,367, No. 315,630 and U.S. Pat. No. 6,319,984 and etc.).
However, the phase transition behavior of the polyphosphazene polymers disclosed in said theses or patents is mainly a sol-precipitation. Also, in case of polymer showing a sol-gel behavior, a gel intensity is weak in a physiological condition or a phenomenon of a gel contraction is generated, thereby having a limitation in being applied as a drug delivering material.